ADAGIO: A Randomized Placebo Controlled Study to Show That Rasagiline May Slow Disease Progression for Parkinson's Disease

• Sponsor: Teva Branded Pharmaceutical Products R&D, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00256204
• Collaborator: (none)
• Enrollment: 1,174
• Arms: 3
• Duration (Months): 43

Study Details

Study Description

Brief Summary

A 2 phase study to evaluate disease progression in Parkinson's disease patients taking rasagiline

Condition or Disease	Intervention/Treatment	Phase
Parkinson's Disease	Drug: Rasagiline Mesylate; Drug: Rasagiline Mesylate; Other: Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 1174 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Multi Center, Double Blind, Randomized Start, Placebo-Controlled, Parallel-Group Study to Assess Rasagiline as a Disease Modifying Therapy in Early Parkinson's Disease Subjects
• Study Start Date: Nov 1, 2005
• Actual Primary Completion Date: Apr 1, 2008
• Actual Study Completion Date: Jun 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1mg rasagiline 1mg early start active treatment arm (72 weeks active)followed by 1mg 36 week delayed start active treatment arm (36 weeks placebo followed by 36 weeks active)	Drug: Rasagiline Mesylate; tablet, 1mg once daily
Experimental: 2mg rasagiline 2mg early start active treatment arm (72 weeks active)followed by 2mg 36 week delayed start active treatment arm (36 weeks placebo followed by 36 weeks active)	Drug: Rasagiline Mesylate; tablet, 2mg once daily
Placebo Comparator: Placebo Each arm is followed by 36 weeks of placebo	Other: Placebo; Placebo

Outcome Measures

Primary Outcome Measures

1. Change in Total Unified Parkinson's Disease Rating Scale (UPDRS) Score From Baseline [12w, 24w, 36w, 42w, 48w, 54w, 60w, 66w, 72w]

   The primary efficacy endpoint was defined as the change in Total UPDRS from Baseline. Subjects were assessed according to the United Parkinson's Disease Rating Scale (UPDRS,(version 3;) Parts I and II are historical data and are designed to rate mentation, behavior and mood; Part III is done as a motor examination at the time of a visit. The UPDRS measures patient status on a scale 0, which is normal or none, to 4, which is severe or the worst scenario.

Secondary Outcome Measures

1. Change in Unified Parkinson's Disease Rating Scale (UPDRS) Score From Baseline to Last Observed Value in the Placebo Phase [36 weeks]

   Subjects were assessed according to the United Parkinson's Disease Rating Scale UPDRS,(version 3;) Parts I and II are historical data and are designed to rate mentation, behavior and mood; Part III is done as a motor examination at the time of a visit. The UPDRS measures patient status on a scale 0, which is normal or none, to 4, which is severe or the worst scenario.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 30 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Men and women with idiopathic PD whose diagnosis is confirmed at screening, with at least two cardinal signs without any other known or suspected cause of parkinsonism. If tremor is not present, subjects must have unilateral onset and persistent asymmetry.

• Subjects with a diagnosis of early idiopathic PD of less than 1½ years duration from time of documented diagnosis.

• Subjects whose clinical condition at the time of enrollment does not require anti-PD treatment and will not require for the next 9 months.

• Willing and able to give informed consent.

Exclusion Criteria:

• Subjects younger than 30 or older than 80 years.

• Subjects with loss of postural reflexes.

• Subjects with UPDRS Tremor score of 3 or greater in any limb.

• Subjects with Hoehn &Yahr Stage III or greater at screening.

• Subjects with freezing while walking.

• Subjects with any of the following features that tend to exclude PD as the cause of

Parkinsonism:

• History of repeated strokes with stepwise progression of Parkinsonian features

• History of repeated head injury or history of definite encephalitis

• Sustained remission

• Supranuclear gaze palsy

• Cerebellar signs

• Early severe autonomic involvement

• Babinski's sign

• Presence of a cerebral tumour or communicating hydrocephalus

• MPTP exposure

• Oculogyric crises

• Subjects who have had previous use of rasagiline or selegiline

• Subjects having used other anti-PD medication basis at any time prior to baseline

• Subjects having used other anti-PD medication (including anticholinergics) for less than 3 weeks during the 3 month period prior to baseline. (not including a single L-Dopa dose as part of L-Dopa test)

• Subjects having used any other anti-PD medication (including anticholinergics) for less than 3 weeks prior to the 3 month period preceding baseline whose anti-PD medication is intentionally ceased in order for the subject to enter the study.

• Subjects who have a clinically significant or unstable medical or surgical condition that may preclude safe and complete participation

• Hypertensive subjects whose BP is not well controlled according to the medical record or as observed during the week of home BP recording prior to baseline

• Subjects diagnosed with melanoma based on the screening dermatologic examination, or with a history of melanoma. Subjects with suspicious lesions at baseline who do not undergo biopsy

• Subjects with significant cognitive impairment as defined by MMSE score < 26

• Subjects with clinically significant psychiatric illness, including major depression [Beck Depression Inventory (short form) ≥15

• Subjects with a history of alcohol or substance abuse within the past 2 years

• Subjects who have taken any experimental medications within 60 days prior to baseline

• Subjects who have used coenzyme Q10 (in daily doses > 300 mg) within 120 days prior to baseline

• Subjects who have used sympathomimetics (including over-the-counter remedies - nasal or oral), dextromethorphan, pethidine or St. John's Wort within the 7 days prior to baseline

• Subjects who have used antidepressants within 42 days prior to baseline

• Subjects who have used ciprofloxacin, a potent CYP 1A2 inhibitor within 7 days prior to baseline

• Subjects who have used MAO inhibitors including reserpine or methyldopa within the three months prior to baseline, or treatment with an anti-emetic or antipsychotic medication with central dopamine antagonist activity within the six months prior to baseline

• Women who are not postmenopausal, surgically sterilized, or using adequate birth control [oral birth control pills, IUD, or a long acting injectable form of contraception; barrier methods alone (i.e., condom) are not sufficient]. Women of childbearing potential without a negative pregnancy test at screening. Nursing women

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Teva Branded Pharmaceutical Products R&D, Inc.

Investigators

• Study Director: Yoni Weiss, MD, Teva Branded Pharmaceutical Products R&D, Inc.

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Unified Parkinsons Disease Ratings Scale
• Unified Parkinson's Disease Rating Scale

Publications

None provided.

• Responsible Party: Teva Branded Pharmaceutical Products R&D, Inc.
• ClinicalTrials.gov Identifier: NCT00256204
• Other Study ID Numbers: TVP-1012/500 (ADAGIO)
• First Posted: Nov 21, 2005
• Last Update Posted: Jan 12, 2012
• Last Verified: Jan 1, 2012

• Keywords provided by Teva Branded Pharmaceutical Products R&D, Inc.: Parkinson's; Rasagiline Mesylate
• Additional relevant MeSH terms: Parkinson Disease; Rasagiline

Study Results

Participant Flow

Arm/Group Title	1mg Delayed Start	1mg Early Start	2mg Delayed Start	2mg Early Start
Arm/Group Description	1mg Rasagiline tablet QD 36 week delayed start active treatment arms (36 weeks placebo followed by 36 weeks Rasagiline)	1mg Rasagiline tablet QD early start active treatment arm (72 weeks active)	2mg Rasagiline tablet QD 36 week delayed start active treatment arms (36 weeks placebo followed by 36 weeks Rasagiline)	2mg Rasagiline tablet QD early start active treatment arm (72 weeks active)
Period Title: Overall Study
STARTED	298	288	295	293
COMPLETED	231	238	241	244
NOT COMPLETED	67	50	54	49

Baseline Characteristics

Arm/Group Title	1mg Delayed Start	1mg Early Start	2mg Early Start	2mg Delayed Start	Total
Arm/Group Description	1mg Rasagiline tablet QD 36 week delayed start active treatment arms (36 weeks placebo followed by 36 weeks Rasagiline)	1mg Rasagiline tablet QD early start active treatment arm (72 weeks active)	2mg Rasagiline tablet QD early start active treatment arm (72 weeks active)	2mg Rasagiline tablet QD 36 week delayed start active treatment arms (36 weeks placebo followed by 36 weeks Rasagiline)	Total of all reporting groups
Overall Participants	298	288	293	295	1174
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	175 58.7%	163 56.6%	169 57.7%	173 58.6%	680 57.9%
>=65 years	123 41.3%	125 43.4%	124 42.3%	122 41.4%	494 42.1%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	61.9 (9.6)	62.4 (9.7)	62.3 (9.6)	62.4 (9.7)	62.2 (9.6)
Sex: Female, Male (Count of Participants)
Female	113 37.9%	113 39.2%	118 40.3%	113 38.3%	457 38.9%
Male	185 62.1%	175 60.8%	175 59.7%	182 61.7%	717 61.1%
Region of Enrollment (participants) [Number]
United States	102 34.2%	91 31.6%	94 32.1%	98 33.2%	385 32.8%
Portugal	4 1.3%	4 1.4%	4 1.4%	4 1.4%	16 1.4%
Spain	12 4%	12 4.2%	12 4.1%	12 4.1%	48 4.1%
Austria	2 0.7%	2 0.7%	2 0.7%	2 0.7%	8 0.7%
Israel	22 7.4%	23 8%	21 7.2%	21 7.1%	87 7.4%
United Kingdom	7 2.3%	7 2.4%	9 3.1%	8 2.7%	31 2.6%
Italy	24 8.1%	25 8.7%	28 9.6%	25 8.5%	102 8.7%
France	11 3.7%	11 3.8%	12 4.1%	14 4.7%	48 4.1%
Hungary	8 2.7%	8 2.8%	6 2%	7 2.4%	29 2.5%
Canada	28 9.4%	27 9.4%	29 9.9%	25 8.5%	109 9.3%
Argentina	17 5.7%	17 5.9%	16 5.5%	18 6.1%	68 5.8%
Romania	25 8.4%	24 8.3%	25 8.5%	24 8.1%	98 8.3%
Germany	27 9.1%	28 9.7%	26 8.9%	28 9.5%	109 9.3%
Netherlands	9 3%	9 3.1%	9 3.1%	9 3.1%	36 3.1%

Outcome Measures

1. Primary Outcome

Title	Change in Total Unified Parkinson's Disease Rating Scale (UPDRS) Score From Baseline
Description	The primary efficacy endpoint was defined as the change in Total UPDRS from Baseline. Subjects were assessed according to the United Parkinson's Disease Rating Scale (UPDRS,(version 3;) Parts I and II are historical data and are designed to rate mentation, behavior and mood; Part III is done as a motor examination at the time of a visit. The UPDRS measures patient status on a scale 0, which is normal or none, to 4, which is severe or the worst scenario.
Time Frame	12w, 24w, 36w, 42w, 48w, 54w, 60w, 66w, 72w

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	1mg Delayed Start	1mg Early Start	2mg Early Start	2mg Delayed Start
Arm/Group Description	1mg Rasagiline tablet QD 36 week delayed start active treatment arms (36 weeks placebo followed by 36 weeks Rasagiline)	1mg Rasagiline tablet QD early start active treatment arm (72 weeks active)	2mg Rasagiline tablet QD early start active treatment arm (72 weeks active)	2mg Rasagiline tablet QD 36 week delayed start active treatment arms (36 weeks placebo followed by 36 weeks Rasagiline)
Measure Participants	298	288	293	295
Week 12	0.9 (4.9)	-1.2 (5.6)	-0.7 (4.8)	0.7 (5.6)
Week 24	3.0 (6.5)	-1.1 (5.6)	-0.5 (5.6)	2.2 (6.5)
Week 36	3.7 (7.2)	0.6 (5.9)	0.8 (6.5)	3.0 (6.9)
Week 42	2.4 (7.4)	0.2 (6.7)	0.4 (7.2)	1.7 (6.6)
Week 48	1.9 (6.9)	0.7 (7.0)	0.5 (7.1)	1.4 (6.8)
Week 54	1.9 (7.3)	0.7 (7.1)	0.8 (7.2)	1.1 (7.0)
Week 60	1.9 (7.5)	1.1 (7.3)	1.2 (7.9)	1.6 (7.4)
Week 66	2.5 (8.1)	1.5 (7.7)	1.5 (8.0)	2.0 (8.2)
Week 72	3.3 (8.9)	1.9 (8.1)	2.2 (8.1)	2.3 (7.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	1mg Delayed Start, 1mg Early Start, 2mg Delayed Start
	Comments	Hypothesis #1: Slopes Superiority of 1mg Rasagiline over Placebo in the PC Phase Where slope is the model estimate of the change from baseline in total UPDRS per week. In this analysis, all available post-baseline observations in the PC Phase of the trial are analyzed (ITT efficacy data analysis set, weeks 12, 24 and 36). The placebo groups for rasagiline 1mg (delayed-start) and 2mg (delayed-start)are combined to one placebo group.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0133
	Comments
	Method	Repeated Measures Mixed Linear Model
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	1mg Delayed Start, 2mg Early Start, 2mg Delayed Start
	Comments	Hypothesis #1: Slopes Superiority of 2mg Rasagiline over Placebo in the PC Phase Where slope is the model estimate of the change from baseline in total UPDRS per week. In this analysis, all available post-baseline observations in the PC Phase of the trial are analyzed (ITT efficacy data analysis set, weeks 12, 24 and 36). The placebo groups for rasagiline 1mg (delayed-start)and 2mg (delayed-start) are combined to one placebo group.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0001
	Comments
	Method	Repeated Measures Mixed Linear Model
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	1mg Delayed Start, 1mg Early Start
	Comments	Hypothesis #2: Superiority of Early over Delayed Start at Week 72 In this analysis, observations of subjects entering the active phase with at least 24 weeks of treatment during the PC Phase and at least one available Total UPDRS measurement during the active-treatment phase from weeks 48, 54, 60, 66 or 72, are analyzed (ACTE data analysis set).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0250
	Comments	The analysis was performed on separate datasets and not on the combined dataset as was pre-specified to account for unexpected interactions of dose level by baseline UPDRS and of dose level by center .
	Method	Repeated Measures
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	2mg Early Start, 2mg Delayed Start
	Comments	Hypothesis #2:Superiority of Early over Delayed Start at Week 72 In this analysis, observations of subjects entering the active phase with at least 24 weeks of treatment during the PC Phase and at least one available Total UPDRS measurement during the active-treatment phase from weeks 48, 54, 60, 66 or 72, are analyzed (ACTE data analysis set.)
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6028
	Comments	The analysis was performed on separate datasets and not on the combined dataset as was pre-specified to account for unexpected interactions of dose level by baseline UPDRS and of dose level by center
	Method	Repeated Measures
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	1mg Delayed Start, 1mg Early Start
	Comments	Hypothesis #3: Slopes Non-Inferiority of Early Start over Delayed Start in the Active Phase. Where slope is the model estimate of the change from baseline in total UPDRS per week. In this analysis, observations of all subjects entering the active phase with at least 24 weeks of treatment during the PC Phase and at least one available Total UPDRS measurement during the active treatment phase from weeks 48, 54, 60, 66 or 72, are analyzed (ACTE data analysis set).
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Non-Inf Test for difference in slopes between treatment groups. One sided 95% CI calculated for difference between slopes of the 1mg early-start group and the 1mg delayed-start group. The inferiority null hypothesis of the early-start group slope over delayed-start group slope is rejected, if the upper limit of one sided 95% CI for difference in slopes does not cross non-inferiority margin of 0.15 UPDRS points per week.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Slope
	Estimated Value	0.000
	Confidence Interval	() 90%; -0.036 to 0.036
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	2mg Early Start, 2mg Delayed Start
	Comments	Hypothesis #3: Slopes Non-Inferiority of Early Start over Delayed Start in the Active Phase. Where slope is the model estimate of the change from baseline in total UPDRS per week. In this analysis, observations of all subjects entering the active phase with at least 24 weeks of treatment during the PC Phase and at least one available Total UPDRS measurement during the active treatment phase from weeks 48, 54, 60, 66 or 72, are analyzed (ACTE data analysis set).
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Non-Inf Test for difference in slopes between treatment groups. One sided 95% CI calculated for difference between slopes of the 2mg early-start group and the 2mg delayed-start group. The inferiority null hypothesis of the early-start group slope over delayed-start group slope is rejected, if the upper limit of one sided 95% CI for difference in slopes does not cross non-inferiority margin of 0.15 UPDRS points per week.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Slope
	Estimated Value	0.029
	Confidence Interval	() 90%; -0.005 to 0.062
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Change in Unified Parkinson's Disease Rating Scale (UPDRS) Score From Baseline to Last Observed Value in the Placebo Phase
Description	Subjects were assessed according to the United Parkinson's Disease Rating Scale UPDRS,(version 3;) Parts I and II are historical data and are designed to rate mentation, behavior and mood; Part III is done as a motor examination at the time of a visit. The UPDRS measures patient status on a scale 0, which is normal or none, to 4, which is severe or the worst scenario.
Time Frame	36 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	1mg Delayed Start	1mg Early Start	2mg Early Start	2mg Delayed Start
Arm/Group Description	+ 2 mg Delayed Start: 36 week combined placebo group.	1mg early start active treatment arm (72 weeks active)	2mg early start active treatment arm (72 weeks active)	+1mg Delayed Start: see 1st column
Measure Participants	588	286	290	0
Mean (Standard Deviation) [Scores on a scale]	3.9 (7.2)	1.0 (6.0)	0.8 (6.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	1mg Delayed Start, 1mg Early Start, 2mg Delayed Start
	Comments	The adjusted means of the changes in Total UPDRS from baseline to LOV in the placebo-controlled phase, observed in the 1 mg and 2 mg rasagiline early-start groups are compared (two contrasts) to the combined placebo group (1 mg and 2 mg rasagiline delayed-start groups), by applying an Analysis of Covariance model. The model includes treatment group, center and baseline Total UPDRS as covariates. For this analysis, both delayed start arms are pooled as a 'placebo arm'
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-3.005
	Confidence Interval	() 95%; -3.857 to -2.153
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	1mg Delayed Start, 2mg Early Start, 2mg Delayed Start
	Comments	The adjusted means of the changes in Total UPDRS from baseline to LOV in the placebo-controlled phase, observed in the 1 mg and 2 mg rasagiline early-start groups are compared (two contrasts) to the combined placebo group (1 mg and 2 mg rasagiline delayed-start groups), by applying an Analysis of Covariance model. The model includes treatment group, center and baseline Total UPDRS as covariates. For this analysis, both delayed start arms are pooled as a 'placebo arm'
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-3.154
	Confidence Interval	() 95%; -4.004 to -2.305
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	2 years, 6 months
Adverse Event Reporting Description	Each Delayed Start arm was preceded by 36 weeks placebo followed by 36 weeks Rasagiline either 1mg or 2mg; therefore, the placebo groups were combined into one group for the placebo analysis.
Arm/Group Title	Placebo Combined Group		1mg Active Treatment		2mg Active Treatment
Arm/Group Description	1mg & 2mg combined placebo group includes those patients in 1mg Delayed start and the 2mg Delayed start arms who received placebo for the first 36 weeks.		1mg Active & 1mg Delayed. This group includes those patients who received 1mg Rasagiline in both the early start active treatment arm (72 weeks active)and those patients who transitioned to active treatment in the 1mg Delayed start treatment arm (36 weeks active treatment)		2mg Active & 2mg Delayed. This group includes those patients who received 2mg Rasagiline in both the early start active treatment arm (72 weeks active)and those patients who transitioned to active treatment in the 2mg Delayed start treatment arm (36 weeks active treatment)
All Cause Mortality
	Placebo Combined Group		1mg Active Treatment		2mg Active Treatment
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo Combined Group		1mg Active Treatment		2mg Active Treatment
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	22/593 (3.7%)		37/288 (12.8%)		44/293 (15%)
Cardiac disorders
Coronary Artery Disease	1/593 (0.2%)	1	0/288 (0%)	0	0/293 (0%)	0
Cardiac failure	1/593 (0.2%)	1	0/288 (0%)	0	0/293 (0%)	0
Angina Pectoris	1/593 (0.2%)	1	1/288 (0.3%)	1	0/293 (0%)	0
Myocardial Infarction	1/593 (0.2%)	1	0/288 (0%)	0	2/293 (0.7%)	2
Atrial Fibrilation	1/593 (0.2%)	1	0/288 (0%)	0	1/293 (0.3%)	1
Atrial Flutter	0/593 (0%)	0	1/288 (0.3%)	1	0/293 (0%)	0
Cardiac Failure Congestive	0/593 (0%)	0	0/288 (0%)	0	1/293 (0.3%)	1
Myocardial Ischaemia	0/593 (0%)	0	1/288 (0.3%)	1	0/293 (0%)	0
Tachycardia	0/593 (0%)	0	1/288 (0.3%)	1	0/293 (0%)	0
Ear and labyrinth disorders
Vertigo	0/593 (0%)	0	1/288 (0.3%)	1	0/293 (0%)	0
Eye disorders
Vitreous Haemorrhage	0/593 (0%)	0	1/288 (0.3%)	1	0/293 (0%)	0
Eyelid Ptosis	1/593 (0.2%)	1	0/288 (0%)	0	0/293 (0%)	0
Cataract	0/593 (0%)	0	1/288 (0.3%)	1	0/293 (0%)	0
Retinal Vein Occlusion	0/593 (0%)	0	0/288 (0%)	0	1/293 (0.3%)	1
Gastrointestinal disorders
Abdominal Pain	1/593 (0.2%)	1	1/288 (0.3%)	1	0/293 (0%)	0
Abdominal Pain Lower	1/593 (0.2%)	1	0/288 (0%)	0	0/293 (0%)	0
Parasthesia Oral	1/593 (0.2%)	1	0/288 (0%)	0	0/293 (0%)	0
Duodenal Ulcer Haemorrhage	0/593 (0%)	0	1/288 (0.3%)	1	0/293 (0%)	0
Gastritis	0/593 (0%)	0	0/288 (0%)	0	1/293 (0.3%)	1
Heus	0/593 (0%)	0	0/288 (0%)	0	1/293 (0.3%)	1
Inguinal Hernia	0/593 (0%)	0	1/288 (0.3%)	1	0/293 (0%)	0
Gastrointestinal Haemorrhage	0/593 (0%)	0	1/288 (0.3%)	1	0/293 (0%)	0
General disorders
Pyrexia	0/593 (0%)	0	2/288 (0.7%)	2	0/293 (0%)	0
Chest Discomfort	1/593 (0.2%)	1	0/288 (0%)	0	0/293 (0%)	0
Chest pain	0/593 (0%)	0	4/288 (1.4%)	4	0/293 (0%)	0
Non-Cardiac Chest Pain	0/593 (0%)	0	1/288 (0.3%)	1	0/293 (0%)	0
Malaise	0/593 (0%)	0	0/288 (0%)	0	1/293 (0.3%)	1
Immune system disorders
Drug Hypersensitivity	0/593 (0%)	0	1/288 (0.3%)	2	0/293 (0%)	0
Infections and infestations
Appendicitis	0/593 (0%)	0	0/288 (0%)	0	1/293 (0.3%)	1
Cellulitis	1/593 (0.2%)	1	1/288 (0.3%)	1	1/293 (0.3%)	1
Labyrinthitis	0/593 (0%)	0	0/288 (0%)	0	1/293 (0.3%)	1
Bronchitis	1/593 (0.2%)	1	0/288 (0%)	0	0/293 (0%)	0
Pneumonia	1/593 (0.2%)	1	2/288 (0.7%)	2	1/293 (0.3%)	1
Urosepsis	0/593 (0%)	0	0/288 (0%)	0	1/293 (0.3%)	1
Laryngitis	0/593 (0%)	0	1/288 (0.3%)	1	0/293 (0%)	0
Diverticulitis	0/593 (0%)	0	1/288 (0.3%)	1	0/293 (0%)	0
Rectal Abscess	0/593 (0%)	0	0/288 (0%)	0	1/293 (0.3%)	1
Peridiverticular Abscess	0/593 (0%)	0	0/288 (0%)	0	1/293 (0.3%)	1
Lower respiratory Tract Infection	0/593 (0%)	0	1/288 (0.3%)	1	0/293 (0%)	0
Erysipelas	0/593 (0%)	0	0/288 (0%)	0	1/293 (0.3%)	1
Injury, poisoning and procedural complications
Femur Fracture	1/593 (0.2%)	1	0/288 (0%)	0	0/293 (0%)	0
Hip Fracture	0/593 (0%)	0	1/288 (0.3%)	1	1/293 (0.3%)	1
Fall	1/593 (0.2%)	1	2/288 (0.7%)	2	0/293 (0%)	0
Femoral Neck Fracture	0/593 (0%)	0	1/288 (0.3%)	1	0/293 (0%)	0
Investigations
Arteriogram Coronary Abnormal	0/593 (0%)	0	1/288 (0.3%)	1	0/293 (0%)	0
Metabolism and nutrition disorders
Hypokalaemia	0/593 (0%)	0	1/288 (0.3%)	1	0/293 (0%)	0
Hyponatraemia	1/593 (0.2%)	1	1/288 (0.3%)	1	0/293 (0%)	0
Dehydration	0/593 (0%)	0	0/288 (0%)	0	2/293 (0.7%)	2
Musculoskeletal and connective tissue disorders
Myalgia	0/593 (0%)	0	1/288 (0.3%)	1	0/293 (0%)	0
Muscle Hemorrhage	0/593 (0%)	0	1/288 (0.3%)	1	0/293 (0%)	0
Osteoarthritis	0/593 (0%)	0	0/288 (0%)	0	3/293 (1%)	3
Back Pain	0/593 (0%)	0	1/288 (0.3%)	1	1/293 (0.3%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Diffuse Large B-Cell Lymphoma	1/593 (0.2%)	1	0/288 (0%)	0	0/293 (0%)	0
Thyroid Neoplasm	1/593 (0.2%)	1	0/288 (0%)	0	0/293 (0%)	0
Endometrial Cancer Stage I	0/593 (0%)	0	0/288 (0%)	0	1/293 (0.3%)	1
Lung Adenocarcinoma Metastic	1/593 (0.2%)	1	0/288 (0%)	0	0/293 (0%)	0
Benign Laryngeal Neoplasm	0/593 (0%)	0	1/288 (0.3%)	1	0/293 (0%)	0
Rectal cancer Metastic	1/593 (0.2%)	1	0/288 (0%)	0	0/293 (0%)	0
Breast cancer	0/593 (0%)	0	1/288 (0.3%)	1	0/293 (0%)	0
Colon Cancer	0/593 (0%)	0	0/288 (0%)	0	1/293 (0.3%)	1
Squamous Cell Carcinoma	0/593 (0%)	0	0/288 (0%)	0	1/293 (0.3%)	1
Ovarian Epithelial Cancer Metastatic	0/593 (0%)	0	1/288 (0.3%)	1	0/293 (0%)	0
Prostrate Cancer	0/593 (0%)	0	1/288 (0.3%)	1	1/293 (0.3%)	1
Renal cancer	0/593 (0%)	0	0/288 (0%)	0	1/293 (0.3%)	1
Basal Cell Carcinoma	0/593 (0%)	0	1/288 (0.3%)	2	1/293 (0.3%)	1
Nervous system disorders
Cerebral Haemorrhage	0/593 (0%)	0	1/288 (0.3%)	1	0/293 (0%)	0
Subarachnoid Haemorrhage	0/593 (0%)	0	0/288 (0%)	0	1/293 (0.3%)	1
Lacunar Infarction	0/593 (0%)	0	0/288 (0%)	0	1/293 (0.3%)	1
Syncope	0/593 (0%)	0	0/288 (0%)	0	1/293 (0.3%)	1
Akinesia	1/593 (0.2%)	1	0/288 (0%)	0	0/293 (0%)	0
Headache	0/593 (0%)	0	0/288 (0%)	0	1/293 (0.3%)	1
Hydrocephalus	0/593 (0%)	0	0/288 (0%)	0	1/293 (0.3%)	1
Parkinson's Disease	0/593 (0%)	0	0/288 (0%)	0	1/293 (0.3%)	1
Carotid Artery Stenosis	0/593 (0%)	0	0/288 (0%)	0	1/293 (0.3%)	1
Loss of Consciousness	0/593 (0%)	0	0/288 (0%)	0	1/293 (0.3%)	1
Sciatica	0/593 (0%)	0	1/288 (0.3%)	1	0/293 (0%)	0
Aphasia	0/593 (0%)	0	1/288 (0.3%)	1	0/293 (0%)	0
Transient Ischaemic Attack	0/593 (0%)	0	1/288 (0.3%)	1	0/293 (0%)	0
Psychiatric disorders
Major Depression	1/593 (0.2%)	1	0/288 (0%)	0	0/293 (0%)	0
Alcohol Abuse	0/593 (0%)	0	0/288 (0%)	0	1/293 (0.3%)	1
Neurosis	0/593 (0%)	0	0/288 (0%)	0	1/293 (0.3%)	1
Hallucination, Visual	0/593 (0%)	0	0/288 (0%)	0	1/293 (0.3%)	1
Suicidal Ideation	0/593 (0%)	0	0/288 (0%)	0	1/293 (0.3%)	1
Renal and urinary disorders
Renal Colic	1/593 (0.2%)	1	0/288 (0%)	0	0/293 (0%)	0
Nephrolithiasis	0/593 (0%)	0	1/288 (0.3%)	1	0/293 (0%)	0
Reproductive system and breast disorders
Laryngeal Leukoplakia	1/593 (0.2%)	1	0/288 (0%)	0	0/293 (0%)	0
Atelectasis	0/593 (0%)	0	1/288 (0.3%)	1	0/293 (0%)	0
Colpocele	0/593 (0%)	0	0/288 (0%)	0	1/293 (0.3%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnoea	1/593 (0.2%)	1	0/288 (0%)	0	1/293 (0.3%)	1
Pulmonary Embolism	0/593 (0%)	0	1/288 (0.3%)	1	0/293 (0%)	0
Pulmonary Infarction	0/593 (0%)	0	1/288 (0.3%)	1	0/293 (0%)	0
Skin and subcutaneous tissue disorders
Hypoaesthesia Facial	1/593 (0.2%)	2	0/288 (0%)	0	0/293 (0%)	0
Rash	0/593 (0%)	0	0/288 (0%)	0	1/293 (0.3%)	1
Surgical and medical procedures
Coronary Artery Bypass	1/593 (0.2%)	1	0/288 (0%)	0	0/293 (0%)	0
Cardioversion	0/593 (0%)	0	1/288 (0.3%)	1	0/293 (0%)	0
Open reduction of fracture	1/593 (0.2%)	1	0/288 (0%)	0	0/293 (0%)	0
Incisional Hernia Repair	0/593 (0%)	0	0/288 (0%)	0	1/293 (0.3%)	1
Inguinal Hernia Repair	0/593 (0%)	0	1/288 (0.3%)	1	1/293 (0.3%)	1
Knee Operation	1/593 (0.2%)	1	0/288 (0%)	0	0/293 (0%)	0
Colon Polypectomy	0/593 (0%)	0	1/288 (0.3%)	1	0/293 (0%)	0
Hysterectomy	0/593 (0%)	0	0/288 (0%)	0	1/293 (0.3%)	1
Abdominal Operation	0/593 (0%)	0	0/288 (0%)	0	1/293 (0.3%)	1
Arterial Stent Insertion	0/593 (0%)	0	1/288 (0.3%)	1	0/293 (0%)	0
Coronary Angioplasty	0/593 (0%)	0	1/288 (0.3%)	1	0/293 (0%)	0
Bone operation	0/593 (0%)	0	0/288 (0%)	0	1/293 (0.3%)	1
Hip Arthroplasty	0/593 (0%)	0	1/288 (0.3%)	1	1/293 (0.3%)	1
Hip Surgery	0/593 (0%)	0	1/288 (0.3%)	1	0/293 (0%)	0
Knee Arthroplasty	0/593 (0%)	0	0/288 (0%)	0	2/293 (0.7%)	2
Cataract Operation	0/593 (0%)	0	1/288 (0.3%)	1	0/293 (0%)	0
Transurethral Prostatectomy	0/593 (0%)	0	1/288 (0.3%)	1	0/293 (0%)	0
Vascular disorders
Hypotension	0/593 (0%)	0	0/288 (0%)	0	1/293 (0.3%)	1
Aortic Aneurysm	0/593 (0%)	0	1/288 (0.3%)	1	1/293 (0.3%)	1
Aortic Aneurysm Rupture	0/593 (0%)	0	1/288 (0.3%)	1	0/293 (0%)	0
Deep Vein Thrombosis	0/593 (0%)	0	1/288 (0.3%)	1	0/293 (0%)	0
Thrombophlebitis	0/593 (0%)	0	0/288 (0%)	0	1/293 (0.3%)	1
Hypertension	0/593 (0%)	0	0/288 (0%)	0	1/293 (0.3%)	1
Other (Not Including Serious) Adverse Events
	Placebo Combined Group		1mg Active Treatment		2mg Active Treatment
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	82/593 (13.8%)		40/288 (13.9%)		34/293 (11.6%)
General disorders
Fatigue	17/593 (2.9%)	18	17/288 (5.9%)	18	10/293 (3.4%)	10
Musculoskeletal and connective tissue disorders
Back Pain	32/593 (5.4%)	34	14/288 (4.9%)	14	15/293 (5.1%)	15
Nervous system disorders
Headache	37/593 (6.2%)	39	14/288 (4.9%)	15	15/293 (5.1%)	15

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Should the Oversight Committee wish to publish the results of this study, the Oversight Committee agrees to provide Teva with a manuscript for review 60 days prior to submission for publication. Teva retains the right to delete from the manuscript confidential information and to object to suggested publication and/or its timing (at the sole discretion of Teva).